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Colistin Plus Sulbactam Or Fosfomycin Against Carbapenem-Resistant Acinetobacter Baumannii: Improved Efficacy Or Decreased Risk of Nephrotoxicity?

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Colistin Plus Sulbactam Or Fosfomycin Against Carbapenem-Resistant Acinetobacter Baumannii: Improved Efficacy Or Decreased Risk of Nephrotoxicity? Infect Chemother. 2021 Mar;53(1):e16 https://doi.org/10.3947/ic.2021.0007 pISSN 2093-2340·eISSN 2092-6448 Original Article Colistin plus Sulbactam or Fosfomycin against Carbapenem-Resistant Acinetobacter baumannii: Improved Efficacy or Decreased Risk of Nephrotoxicity? Weerayuth Saelim 1, Dhitiwat Changpradub 2, Sudaluck Thunyaharn 3, Piraporn Juntanawiwat 4, Parnrada Nulsopapon 1,5, and Wichai Santimaleeworagun 1,5 1Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand 2Division of Infectious Diseases, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand Received: Jan 17, 2021 3Faculty of Medical Technology, Nakhonratchasima College, Nakhon Ratchasima, Thailand Accepted: Mar 7, 2021 4Division of Microbiology, Department of Clinical Pathology, Phramongkutklao Hospital, Bangkok, Thailand 5Antibiotic Optimization and Patient Care Project by Pharmaceutical Initiative for Resistant Bacteria and Corresponding Author: Infectious Diseases Working Group [PIRBIG] Wichai Santimaleeworagun, PhD Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand. ABSTRACT Tel: +66 (0) 3442 55800 Fax: +66 (0) 342 55801 Background: Acinetobacter baumannii has been recognized as a cause of nosocomial infection. E-mail: [email protected] To date, polymyxins, the last-resort therapeutic agents for carbapenem-resistant A. baumannii Copyright © 2021 by The Korean Society (CRAB). Thus, the small number of effective antibiotic options against CRAB represents a of Infectious Diseases, Korean Society for challenge to human health. This study examined the appropriate dosage regimens of colistin Antimicrobial Therapy,Provisional and The Korean Society alone or in combination with sulbactam or fosfomycin using Monte Carlo simulation with for AIDS the aims of improving efficacy and reducing the risk of nephrotoxicity. This is an Open Access article distributed under the terms of the Creative Commons Materials and Methods: Clinical CRAB isolates were obtained from patients admitted to Attribution Non-Commercial License (https:// Phramongkutklao Hospital in 2014 and 2015. The minimum inhibitory concentration (MIC) creativecommons.org/licenses/by-nc/4.0/) of colistin for each CRAB isolate was determined using the broth dilution method, whereas which permits unrestricted non-commercial those of sulbactam and fosfomycin were determined using the agar dilution method. Each use, distribution, and reproduction in any drug regimen was simulated using the Monte Carlo technique to calculate the probability medium, provided the original work is properly cited. of target attainment (PTA) and the cumulative fraction of response (CFR). Nephrotoxicity based on RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) ORCID iDs criteria was indicated by colistin trough concentration exceeding ≥3.3 µg/mL. Weerayuth Saelim Results: A total of 50 CRAB isolates were included. The MIC50 and MIC90 were 64 and 128 https://orcid.org/0000-0001-5839-440X Provisional Dhitiwat Changpradub µg/mL, respectively, for sulbactam, 256 and 2,048 µg/mL, respectively, for fosfomycin, and https://orcid.org/0000-0001-7939-6834 1 and 4 µg/mL, respectively, for colistin. In patients with creatinine clearance of 91 – 130 Sudaluck Thunyaharn m/min, the dosing regimens of 180 mg every 12 h and 150 mg every 8 h achieved ≥ 90% https://orcid.org/0000-0002-6836-8755 of target of the area under the free drug plasma concentration–time curve from 0 to 24 hr Piraporn Juntanawiwat (fAUC24)/MIC ≥25 against isolates MICs of ≤0.25 and ≤0.5 µg/mL, respectively, and their https://orcid.org/0000-0002-8543-8428 rates of colistin trough concentration more than ≥3.3 µg/mL were 35 and 54%, respectively. Parnrada Nulsopapon https://orcid.org/0000-0002-0738-214X Colistin combined with sulbactam or fosfomycin decreased the colistin MIC of CRAB Wichai Santimaleeworagun isolates from 1 – 16 µg/mL to 0.0625 – 1 and 0.0625 – 2 µg/mL, respectively. Based on CFR https://orcid.org/0000-0001-9974-957X ≥ 90%, no colistin monotherapy regimens in patients with creatinine clearance of 91 – 130 mL/min were effective against all of the studied CRAB isolates. For improving efficacy and https://icjournal.org 1/13 Colistin combinations against drug-resistant A. baumannii Conflict of Interest reducing the risk of nephrotoxicity, colistin 150 mg given every 12 h together with sulbactam No conflicts of interest. (≥6 g/day) or fosfomycin (≥18 g/day) was effective in patients with creatinine clearance of 91 Author Contributions – 130 mL/min. Additionally, both colistin combination regimens were effective against five Conceptualization: DC, ST, WiS. Data curation: colistin-resistant A. baumannii isolates. WeS, WiS, PN. Formal analysis: WeS, WiS, PN. Conclusion: Colistin monotherapy at the maximum recommended dose might not cover Funding acquisition: WiS. Investigation: DC, some CRAB isolates. Colistin combination therapy appears appropriate for achieving the ST, WiS. Methodology: DC, ST, WiS. Project pharmacokinetic/pharmacodynamic targets of CRAB treatment. administration: WiS. Resources: DC, ST, PJ. Software: WiS. Supervision: DC, ST, PJ, WiS. Keywords: Colistin resistance; Colistimethate; Combination; Synergism Validation: WeS, WiS, PN. Visualization: DC, ST, WiS. Writing - original draft: WiS. Writing - review & editing: WeS, DC, ST, PJ, PN. INTRODUCTION Acinetobacter baumannii has been recognized as a cause of nosocomial infection because of its resistance to multiple classes of antibiotics, especially carbapenems, and the microbe exhibits long-term survival in healthcare settings [1]. To date, polymyxins, the last-resort therapeutic agents for carbapenem-resistant A. baumannii (CRAB), have been sporadically used [2, 3]. Thus, the small number of effective antibiotic options against CRAB represents a challenge to human health. In data from the National Antimicrobial Resistance Surveillance Thailand Center, A. baumannii was the third-most common gram-negative bacterium and fifth-most common bacterium overall isolated from blood specimens in 2019. Unfortunately, more than half of A. baumannii isolates are carbapenem-resistant, whereas few strains are resistant to colistin (colistin resistant A. baumannii; CoRAB) [4]. Currently, polymyxins including polymyxin B and colistin (polymyxin E) are important treatments for CRAB, which displayed extensive resistance to other antimicrobials. However, Provisionalthe emergence of strains with elevated colistin minimum inhibitory concentrations (MICs) and polymyxin resistance has been documented, and polymyxin monotherapy has failed to meet pharmacokinetic/pharmacodynamic (PK/PD) targets [2, 3]. Polymyxins in combination with other agents are often used in the empirical treatment of CRAB infection, and novel treatment options are needed to increase antimicrobial activity and reduce the development of resistance in extensively drug-resistant A. baumannii isolates [3, 5, 6]. Jitaree et al. determined the optimal colistin monotherapy regimen using Monte Carlo simulations. They found that at an MIC of 1 µg/mL, only a daily dose of at least 450 mg could achieve 90% probability of target attainment (PTA) of the area under the unbound colistin plasmaProvisional concentration–time curve (fAUC)/MIC ratio ≥25 among patients with creatinine clearance ≥80 mL/min [7]. Conversely, the most A. baumannii isolates had MICs of 1 - 2 µg/mL [6]. Thus, combination regimens with synergistic effects might result in better efficacy and prevent the need for high colistin doses, which increase the risk of nephrotoxicity. Together, the previous data indicated that the trough concentrations of colistin more than 3.3 µg/mL were a predictor for occurrence of acute kidney injury (AKI) [8]. Sulbactam, a beta-lactamase inhibitor, has exhibited activity against CRAB. However, high doses were recommended because of its higher MICs in CRAB isolates. According to Saelim et al., only the maximum daily recommended dose of sulbactam (12 g) delivered using a 2 - 4h infusion or continuous infusion was effective against all isolates with sulbactam MICs of 96 µg/ https://icjournal.org https://doi.org/10.3947/ic.2021.0007 2/13 Colistin combinations against drug-resistant A. baumannii mL based on meeting the PTA or cumulative fraction of response (CFR) target of the percentage of free drug time exceeding the MIC (fTime/MIC). Conversely, 118 CRAB isolates in the study had minimum inhibitory concentration required to inhibit the growth of 50% of organisms (MIC50) and MIC90 values of 64 and 192 µg/mL, respectively, for sulbactam [9]. Therefore, monotherapies such as colistin and sulbactam failed to achieve the PK/PD targets. To date, colistin combinations have been recommended to treat CRAB because most strains remain sensitive to polymyxins [10]. Vardakas et al. evaluated the benefit of colistin in combination with other antibiotics to reduce mortality compared with the effects of colistin monotherapy. A significantly lower death rate was observed for the colistin combination regimen in patients with bloodstream infections and in patients with Acinetobacter infections [11]. Certain studies focused on determining the synergistic effects of colistin plus sulbactam or fosfomycin against A. baumannii [5, 6]. Our previous study revealed colistin plus sulbactam and colistin plus fosfomycin regimens had synergistic or additive effects against 53.3 and 73.3% of isolates, respectively. No antagonistic effect was observed for any colistin-based
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